The insulin-like growth factors (IGF-I and -II) are important determinants of fetal growth and postnatal development. Baker, J., et al. Cell 75, 73-82 (1993); and Stewart, C. E. H., and Rotwein, P. Physiol. Rev. 76, 1005-1026 (1996). IGF bioactivity is modulated by IGF binding proteins (IGFBPs), which, in turn, are regulated by specific proteases. Clemmons, D. R. Cytokine Growth Factor Rev. 8, 45-62 (1977); and Fowlkes, J. L. Trends Endocrinol. Metab. 8, 299-306 (1997).
PAPP-A increases IGF bioavailability and mitogenic effectiveness in vitro through regulated cleavage of IGFBP-4. PAPP-A is a large placental glycoprotein, present in the serum of pregnant women in increasing concentrations throughout pregnancy. PAPP-A in pregnancy serum is linked via a disulfide bond to the proform of eosinophil major basic protein (proMBP), forming an approximately 500 kDa 2:2 complex, denoted PAPP-A/proMBP. The serum form of PAPP-A is derived from a pre-proprotein containing a putative 22-residue signal peptide, a pro-part of 58 residues, and a 1547-residue circulating mature polypeptide. The amino acid sequence shows no global similarity to any known protein, but it contains two sequence motifs common to the metzincins, a superfamily of metalloproteases, three Lin-12/Notch repeats known from the Notch protein superfamily, and five short consensus repeats known from components of the complement system. Free PAPP-A cannot be isolated from pregnancy serum, but can be isolated in conditioned media from human fibroblasts.
The PAPP-A/proMBP complex is absent from maternal serum in pregnancies where the mother is carrying a fetus with Cornelia de Lange syndrome. Recently, PAPP-A and proMBP in conjunction with SP1 have been shown to be effective markers for detecting fetuses affected with Down's syndrome in weeks 7-12 of gestation.